Health and Disease , In 1999 the international team of scientists participating in the $3 billion Human Genome Project made impressive strides toward the goal of locating, analyzing, and identifying virtually every one of the estimated 100,000 human genes. On December 1 it was announced that cooperating scientists from four institutions had meticulously mapped 97% of the genetic material contained on chromosome 22. As Francis Collins, chairperson of the publicly funded international project, noted, “This is the first time that we’ve had a complete chapter in the human construction book.” Mutation to genes located on chromosome 22 were known to play a role in several dozen human diseases, including disorders of the heart and immune system, certain cancers, mental retardation, and schizophrenia. Although chromosome 22 represents only about 1.1% of the genes in the human body, the scientists involved in the decoding effort expected to complete a “first draft” of the entire genome project early in 2000—several years ahead of the originally projected completion date.

A major bioethical debate during the year centred on research using human embryonic stem and germ cells, both first isolated in late 1998. While such research held great promise for scientific advances, it also raised serious ethical questions. (See Special Report: The Science and Ethics of Embryonic Stem Cell Research.)

In October the Washington Post surveyed about 2,000 Americans to find out what issues were worrying them most. From a list of 51 possible “worries,” the single greatest concern, irrespective of political leanings, was that “insurance companies are making decisions about medical care that doctors and patients should be making.” Two other health care issues ranked among the respondents’ top five worries—that elderly Americans would not be able to afford the prescription drugs they need and that the respondents’ current medical benefits would be reduced or eliminated.

Americans had good reason to fear the power of insurance companies when in June the U.S. Justice Department’s antitrust division approved the takeover of Prudential Health Care by Aetna, Inc., creating the nation’s largest managed-care company. A spokesman for the group Consumers for Quality Care called the takeover “a black eye for the Clinton Administration in terms of patient protection.”

Americans worried about health care may have gained some relief in November when the UnitedHealth Group, which insured 14.5 million people—8.7 million in managed-care plans—announced that it would let doctors make their own decisions on care. The Minneapolis, Minn.-based insurer would no longer interfere with physicians’ treatment choices, including the decision to hospitalize a patient. Physicians’ groups hailed the step. Thomas Reardon, president of the American Medical Association, called it “historic” and “a long overdue victory for American patients and the care they receive.”

AIDS.

Thanks to the wide use and effectiveness of so-called highly active antiretroviral therapy (HAART)—potent combinations of anti-HIV medications—in industrialized countries many people with HIV/AIDS were living longer and healthier lives. Several studies published in 1999, however, pointed to the inherent limitations of HAART. One study showed that even though some people who had taken the drugs had the amount of HIV in their blood reduced to near-undetectable levels, the virus continued to lurk in their immune systems. The finding suggested that people who responded to HAART might need to keep taking the drugs indefinitely. Moreover, those same people remained capable of transmitting the virus, despite their apparent wellness.

Another study shed important new light on the earliest stages of HIV infection. It found that almost as soon as the virus invades the body, it establishes a “reservoir of infection” that is especially refractory to attack by antiviral drugs and the body’s own immune system. The finding was viewed as a setback for those seeking to create an AIDS vaccine. Yet another disheartening discovery was that about one-sixth of new HIV infections were drug-resistant.

Although AIDS death rates in the U.S. were declining, the rate of new HIV infections was a cause for concern. From July 1998 through June 1999, a total of 47,083 HIV/AIDS cases were reported in the U.S. Notably high rates were seen in African Americans, Hispanics, and women. In late November UNAIDS, the United Nations agency charged with combating the spread of HIV/AIDS, reported 2.6 million deaths from AIDS worldwide in 1999 and 5.6 million new HIV infections. According to Peter Piot, the agency’s executive director, “The epidemic is far from over. The crisis is actually growing.”

The gloomiest AIDS news came from the less-developed world. In sub-Saharan Africa an estimated 22.5 million adults and 1 million children of the region’s 600 million people were HIV-infected. Those unprecedented rates had reduced life expectancy from 64 to 47 years. Only two African countries, Uganda and Senegal, were effectively controlling the spread of AIDS. (See Special Report: Africa’s Struggle Against AIDS.)

In January an international team of researchers reported that they had traced the origin of the AIDS virus to a subspecies of chimpanzee in Gabon. Specifically, the team found that HIV-1, the virus that had caused the overwhelming majority of the world’s estimated 34 million AIDS cases to date, was originally transmitted to humans by chimpanzees of the subspecies Pan troglodytes troglodytes. (HIV-2, which causes a milder and far-less-common form of AIDS, previously had been linked to a species of African monkey.) The path to the latest discovery involved conducting sophisticated genetic tests on viruses isolated from four chimpanzees that carried a simian virus nearly identical to HIV-1; the infected primates, however, did not become ill. Scientists speculated that humans living in the native habitat of the chimpanzee subspecies contracted the virus through exposure to the blood of butchered animals, but they could not explain how a microbe that had such a benign effect in the apes became so virulent when it infected humans.

Infectious Diseases.

According to the World Health Organization (WHO), the top six infectious killers worldwide, ranked by the number of lives they took in 1998, were acute respiratory infections, including influenza and pneumonia (3.5 million), AIDS (2.3 million), diarrheal diseases (2.2 million), tuberculosis (1.5 million), malaria (1.1 million), and measles (900,000). A report issued by WHO in 1999 described “an infectious disease crisis of global proportions,” accounting for 13.3 million of the 53.9 million deaths worldwide in 1998. It noted that infectious diseases were the biggest killer of children and young adults and that one in two deaths in less-developed countries had an infectious cause. The report also pointed out that the situation had worsened as a result of mass population movements; in particular, refugees and displaced persons, who were highly vulnerable to infection, were readily spreading infectious diseases into new areas. In addition, the report emphasized that the arsenal of drugs available to treat infectious diseases was being progressively depleted owing to the growing drug resistance of microbes.

Outbreaks of infectious disease occurred across the globe, some more alarming than others. In April Angola experienced an outbreak of paralytic poliomyelitis. In response, WHO mounted an emergency campaign to immunize 700,000 Angolan children against the highly contagious disease. Although there remained a few “hot spots” for polio in Africa and Asia, WHO still aimed for global eradication of the disease by the end of 2000. Its eradication campaign, launched in 1988, had been monumentally successful in most of the world.

Probably the most publicized infectious disease outbreak in 1999 was one in New York City that was responsible for only about 50 cases of human illness and fewer than 10 deaths. In August a mosquitoborne illness initially thought to be St. Louis encephalitis killed scores of domestic and exotic birds, particularly crows; it also caused serious illness and brain inflammation in a few humans. In September epidemiologists confirmed that the responsible microbe was a virus similar to one that causes West Nile fever, an illness never previously seen in the Western Hemisphere. The original source of the outbreak was not known; one speculation, however, was that the disease reached the U.S. through illicitly imported African birds. The New York epidemic was effectively brought under control when the city mounted an all-out ground and aerial insecticide-spraying effort and advised city dwellers to protect themselves from mosquitoes.

As in other recent years, a large number of infectious outbreaks in 1999 were traced to human consumption of contaminated food. In one of the biggest food-poisoning incidents, more than 1,000 people who had attended a county fair in upstate New York were infected with a deadly strain of Escherichia coli. The source was a well that had been contaminated by runoff from cow manure; fairgoers presumably consumed water from the well in the form of ice in soft drinks, lemonade, snow cones, and other refreshments. Although many became seriously ill, only two people died—a 3-year-old girl and a 79-year-old man.

In Denmark 25 confirmed cases of virulent salmonella infection occurred in people who had eaten meat from infected pigs; 11 were hospitalized and 2 died. Their strain had reduced susceptibility to treatment with an important class of antibiotics (fluoroquinolones). The outbreak caused considerable alarm among infectious-disease experts worldwide. It was recognized that when pigs and other farm animals are given antibiotics to eliminate infection and enhance growth—a commonplace practice—bacteria grow increasingly resistant to the drugs. The scientists who investigated this outbreak called for sharp restrictions on the use of fluoroquinolones in food animals.

In October, about a year after a new vaccine for children was licensed in the U.S., it was withdrawn by its American manufacturer. The vaccine, Rotashield, was designed to protect against a potentially fatal diarrheal illness caused by rotavirus. In the late 1990s rotavirus caused about three million cases of illness annually in the U.S. alone and killed an estimated 600,000 children worldwide. At the time the vaccine was licensed, a federal health-advisory panel recommended three doses of Rotashield before a child’s first birthday. Subsequently, however, the vaccine was found to be responsible for a potentially fatal bowel obstruction in dozens of babies who had received it.

The year was also one of major achievements in the conquest of infectious diseases. On October 6 WHO acknowledged a public health triumph that could never have been achieved without the intimate collaboration of the public and private sectors. As recently as the 1970s, the disease known as onchocerciasis, or river blindness, annually robbed hundreds of thousands of West Africans of their sight. The disease agent, a parasitic worm, is transmitted by the bite of blackflies that breed in fast-flowing rivers. To wipe out onchocerciasis, WHO, the Carter Center in Atlanta, Ga., and more than 20 donor countries and agencies teamed up with Merck & Co., a major pharmaceutical manufacturer. Merck donated a veterinary drug, ivermectin (Mectizan), which effectively prevented sight loss in people living in endemic areas; a single pill offered protection for about a year. Thanks to the cooperative campaign, which started in 1974, an estimated 12 million children who would have been at high risk of becoming blind were spared that fate. Programs to eliminate river blindness were under way in other parts of Africa and in six countries in Latin America.

At its peak in the early 1940s, measles affected almost 900,000 people annually in the U.S. and killed more than 2,000. In 1998 there were only 100 confirmed U.S. cases of the vaccine-preventable viral illness, 71% of which were imported from other countries. In 1999, although it remained a major infectious killer globally, measles was on its way to being eradicated in the U.S.

In 1999 two new drugs, one inhaled (zanamivir [Relenza]) and one in pill form (oseltamivir [Tamiflu]), were approved for treating the two common strains of influenza virus (types A and B). The drugs were the first of a new class of antiviral compounds called neuraminadase inhibitors. Studies showed that zanamivir was 80% effective in preventing flu. It also reduced the duration of flu symptoms by a day or two. Oseltamivir was similarly effective, preventing flu in up to 84% of adults who took the medication once daily for six weeks. Many physicians questioned whether use of the new drugs would be cost-effective, and infectious-disease experts emphasized that inexpensive, widely available vaccines at the beginning of the flu season remained the best protection.

Aging

A study published in the journal Nature in July raised considerable hope about the possibility of preventing Alzheimer’s disease with a vaccine. Researchers at the San Francisco firm Elan Pharmaceuticals vaccinated mice that had been genetically programmed to overproduce amyloid, a protein-carbohydrate complex that forms harmful deposits in the brain, known as plaques. Amyloid plaques are a hallmark of Alzheimer’s disease. In young healthy mice the vaccine prevented the formation of brain-clogging plaques altogether, and in older mice it prevented further progression of existing plaques.

Cancer

Multiple myeloma is a severe, often fatal cancer of the bone marrow. In the 1990s treatment typically involved massive doses of chemotherapeutic drugs, but even after the most rigorous therapy, patients commonly relapsed. The five-year survival rate for treated patients was only about 29%. In a trial extending over several years, oncologists at the University of Arkansas treated 84 multiple myeloma patients with advanced disease with thalidomide, a drug developed in the 1950s (and notorious for having caused birth deformities in infants born of mothers who had taken it during early pregnancy). One-third of the myeloma patients were helped, and two patients experienced complete remission. Experts considered such results “remarkable.” In studies under way at the end of the year, researchers were hoping to learn why thalidomide worked so well in some patients and not at all in others.

In 1997 research pioneer Judah Folkman of Children’s Hospital in Boston showed that two recently discovered substances, angiostatin and endostatin, could shrink and in some cases obliterate malignant tumours—even massive ones—in mice. These natural proteins worked by inhibiting the angiogenesis, or blood vessel development, that provides tumours with their own blood supply and thereby allows them to grow from tiny, harmless masses into large, spreading malignancies. Folkman’s studies generated enormous excitement among cancer treatment specialists and the public alike. At first, other scientists failed to duplicate his results, but in early 1999 researchers in several laboratories across the U.S. succeeded in suppressing mouse tumours with angiogenesis inhibitors. Moreover, during the year Folkman and his colleagues achieved the impressive feat of using endostatin to eliminate human prostate cancers that had been implanted in mice. In October the first human trials of endostatin began at Boston’s Dana-Farber Cancer Institute. They were Phase I trials to determine the safety of the drug and the dose at which it should be given.

A common and often fatal cancer of women was the focus of attention in February. Officials at the U.S. National Cancer Institute notified cancer specialists around the world of a major advance in the treatment of cervical cancer. Five separate studies had shown that a combination of chemotherapy and the standard treatment, radiation, reduced cervical cancer death rates by 30–50%. Experts speculated that the combined treatment worked so well because the drugs made cancer cells more vulnerable to radiation.

In the less-developed world, cervical cancer killed more women than any other cancer, largely because the women lacked access to an inexpensive and accurate screening method. Whereas about 70% of women in industrialized countries received routine Pap smears, only about 5% in less-developed countries had such tests. Researchers in Zimbabwe, however, developed a “low-tech” means of diagnosing cervical abnormalities quite accurately at an early stage. By simply swabbing a woman’s cervix with vinegar, then checking the cervix visually to see if any cells turned white, they found it possible to detect precancerous or at least suspicious lesions. Women with suspected abnormalities could then be referred for a more decisive test such as a biopsy.

Cardiovascular Disease

On rare occasions a clinical trial involving a large number of subjects is terminated early because the preliminary results are so dramatic. This was the case in November when an international team of cardiovascular researchers realized the lifesaving potential of the drug ramipril (Altace) for a broad array of patients at high risk for heart attack, stroke, or death from cardiovascular causes. In the trial one group took ramipril, an angiotensin converting enzyme (ACE) inhibitor; the other group received a placebo. Less than four years into the trial (scheduled to last five years), the treated group had significantly lower rates of death, heart attack, and stroke than those in the placebo group. Ramipril was not a new drug but one that had been used successfully for nearly a decade to treat high blood pressure. (As an ACE inhibitor, the drug relaxes blood vessels and thereby lowers blood pressure and decreases the heart’s workload.) Because of the “potential therapeutic implications” for so many patients, The New England Journal of Medicine took the uncommon step of posting the study’s findings on the Internet (www.nejm.org) three months before the final version of the report was scheduled for publication.

Antioxidants in Disease Prevention

Blueberries, pomegranates, green tea, and cabernet wine were among many antioxidant-rich foods and drinks shown to prevent disease in 1999. Antioxidants prevent the damage done to cells by free radicals, molecules that are released during the normal metabolic process of oxidation. Oxidation can lead to cancerous changes, accelerate the aging process, and contribute to heart disease and degenerative diseases such as arthritis.

Although it did not go so far as to state that “ketchup prevents cancer,” a major report in the Journal of the National Cancer Institute concluded that people who consumed large amounts of “tomatoes and tomato products [were] at a substantially decreased risk of numerous cancers, although probably not all cancers.” Researchers at Harvard Medical School analyzed 72 studies that had looked at the link between tomato consumption and cancer; 35 of those studies found a statistically significant reduction in risk, while 15 were inconclusive or showed a slight reduction. A number of the studies had focused in particular on lycopene, the nutrient in tomatoes that acts as a powerful antioxidant and also gives the fruit its red colour. The cancers most commonly prevented were those of the prostate, lung, and stomach, but there was also evidence that pancreatic, colorectal, esophageal, oral, breast, and cervical cancers were prevented with tomato consumption. Raw and cooked tomatoes and processed tomato products that did not contain excessive sugar or unhealthy fats were all found to be beneficial.

A study published in the Journal of the American Medical Association found that the consumption of at least five servings a day of fruits and vegetables—in particular citrus fruits and juices, leafy green vegetables, and cruciferous vegetables such as broccoli, cabbage, and turnip—cut the risk of ischemic stroke by 30%. (Ischemic stroke occurs when blood clots block the flow of blood to the brain, which results in brain injury or death.) The study also found that drinking a single glass of orange juice a day lowered stroke risk by 25%. Juice manufacturers wasted no time in advertising this finding.

Obesity

A recently published survey of American adults found that the prevalence of obesity (defined as a body-mass index [BMI] of 30 or more) increased from 12% of the population in 1991 to 18% at the end of 1998. (BMI is determined by dividing one’s weight in kilograms by the square of one’s height in metres.) A second survey found that about half of the U.S. population was overweight (having a BMI of 25 or higher) and that excess weight was strongly associated with chronic diseases, including high blood pressure, high blood cholesterol, type II (non-insulin-dependent) diabetes, gallbladder disease, coronary heart disease, and osteoarthritis.

Orlistat (Xenical), a new drug for the treatment of obesity, was approved by the U.S. Food and Drug Administration in April. Unlike most other medications for weight loss, orlistat works in the intestine, where it blocks about one-third of the fat a person consumes from being absorbed; undigested fat is eliminated in feces. Orlistat was designed to be used in conjunction with a reduced-fat, reduced-calorie diet. In clinical trials subjects taking orlistat for one year lost an average of 6.1 kg (13.4 lb), whereas those on a reduced-calorie diet alone lost 2.6 kg (5.8 lb). Side effects were mainly gastrointestinal (e.g., diarrhea, oily stools, and flatulence). Although the drug was a prescription item and meant for people who were at least 20% overweight, orlistat was widely advertised to the general public and available over the Internet after an on-line medical “consultation.”

U.S. Failures

Reports issued at the end of the year drew attention to critical failures in the U.S. health care system. A committee of the Institute of Medicine found “stunningly high rates of medical errors—resulting in deaths, permanent disability, and unnecessary suffering.” Calling such mistakes “unacceptable in a medical system that promises first to ‘do no harm,’” the committee drew up a comprehensive strategy to reduce medical errors by 50% over five years.

A scathing report issued by U.S. Surgeon General David Satcher noted that mental illness affected one in five Americans and that more than half of those who needed treatment did not get it. The report, posted on the Internet (www.surgeongeneral.gov), was critical of insurance policies that did not provide adequate coverage for mental illness and of American society, which continued to stigmatize the illness.